The present invention provides a process for making enantiomerically enriched 4-piperidinylglycine.
4-Piperidinylglycine is an important amino acid which has been used in synthesizing pharmaceutical ingredients such as matrix metalloproteinase inhibitor and thrombin inhibitor. While racemic piperidinylglycine has been synthesized by hydrogenation of an enamide substrate, enantiomerically enriched piperdinylglycine is much more difficult to synthesize.
U.S. Pat. No. 5,817,822 describes an enantioselective synthesis of (R)-N-t-Boc-4-piperidinylglycine using optically active (R)-4-benzyl-2-oxazolidinone as a chiral auxiliary. (R)-N-t-Boc-4-piperidinylglycine is prepared by an 8-step synthetic sequence utilizing R-(+)-4-benzyl-2-oxazolidinone as a chiral auxiliary and trisyl azide as an electrophile. This method works well for the preparation of small quantities of 4-piperidinylglycine for drug discovery activities, however, for scale up synthesis, this method is economically unsatisfactory due to the many steps involved, and potentially unsafe due to the handling of 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide), which is thermally unstable.
Chiral rhodium catalysts have been used in asymmetric synthesis of heterocyclic amino acids as described by Burk, M. J.; Gross, M. F.; Martinez, J. P. in J. Am. Chem. Soc., 117, 9375-9376 (1995); Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. in Organic Letters, 2, 3421-3423 (2000); Tiffin, P. D.; Jones, S. W.; Palmer, C. F.; Paul, J. M. in Tetra. Lett., 40, 1211-1214 (1999).
Therefore, it is desirable to develop a more direct synthesis for 4-piperidinylglycine which does not involve using 2,4,6-triisopropylbenzenesulfonyl azide.
The invention provides a process for making enantiomerically enriched 4-piperidinylglycine having the formula (I) 
said process comprising
(a) combining N-protected glycine ester having the formula (II) 
xe2x80x83with 4-piperidone having the formula (III) 
xe2x80x83whereby didehydroamino acid ester is formed having the formula (IV); 
(b) reducing the didehydroamino acid ester (IV) with hydrogen gas in the presence of a catalyst selected from the group consisting of (R,R)-BPE-Rh having the formula (A1), (S,S)-BPE-Rh having the formula (A2), (R,R)-Me-DuPHOS-Rh having the formula (B1), (S,S)-Me-DuPHOS-Rh having the formula (B2), and combinations thereof; 
xe2x80x83whereby a protected chiral compound is formed having the formula (V); 
(c) removing the protecting groups of formula (V), whereby the 4-piperidinylglycine having the formula (I) is formed;
wherein R1 is selected from the group consisting of hydrogen and PO(OM)2, wherein M is a phenyl or C1-C8 linear, branched or cyclic alkyl group; R2 is selected from the group consisting of hydrogen, phenyl and a C1-C8 linear, branched or cyclic alkyl group; R3 and R4 are independently selected from the group consisting of hydrogen, phenyl, a C1-C8 linear, branched or cyclic alkyl group, and OR6, wherein R6 is selected from the group consisting of hydrogen, phenyl, benzyl, substituted benzyl, and C1-C8 linear, branched or cyclic alkyl group; R5 is independently selected from the group consisting of a C1-C8 linear, branched or cyclic alkyl group, a C1-C8 linear, branched or cyclic fluoroalkyl group, and combinations thereof; diene is a counter ligand independently selected from the group consisting of cyclooctadiene (COD) and norbornadiene (NBD); Axe2x88x92 is an anion wherein A is independently selected from the group consisting of trifluoromethanesulfonate (OTf), tetrafluoroborate (BF4), hexafluoroantimonate (SbF6) and hexafluorophosphate (PF6); Xxe2x88x92 is an anion wherein X is independently a halogen; and xe2x80x9c*xe2x80x9d designates an asymmetric carbon having (R)- or (S)-configuration.
The process of the invention yields an enantiomerically enriched 4-piperidineglycine in excellent yield. As used herein, xe2x80x9cenantiomerically enrichedxe2x80x9d 4-piperidinylglycine means at least 60% enantiomeric excess, preferably at least 80% entantiomeric excess, most preferably at least 98% enantiomeric excess, of 4-piperidinylglycine.
The process of the invention is used to prepare 4-piperidinylglycine having the formula (I) 
wherein Xxe2x88x92 is an anion wherein X is independently a halogen; and xe2x80x9c*xe2x80x9d designates an asymmetric carbon having (R)- or (S)-configuration. Preferably the halogen is chlorine. The process involves at least three steps. In the first step, Step (a), N-protected glycine ester having the formula (II) 
xe2x80x83is combined with 4-piperidone having the formula (III) 
xe2x80x83to form didehydroamino acid ester having the formula (IV); 
wherein R1 is selected from the group consisting of hydrogen and PO(OM)2, wherein M is a phenyl or C1-C8 linear, branched or cyclic alkyl group. Preferably, R1 is PO(OCH3)2. R2 is selected from the group consisting of hydrogen, phenyl and a C1-C8 linear, branched or cyclic alkyl group. Preferably R2 is methyl. R3 and R4 are independently selected from the group consisting of hydrogen, phenyl, a C1-C8 linear, branched or cyclic alkyl group, and OR6, wherein R6 is selected from the group consisting of hydrogen, phenyl, benzyl, substituted benzyl, and C1-C8 linear, branched or cyclic alkyl group. Preferably, R3 is OCH2Ph. Preferably, R4 is OC(CH3)3. Xxe2x88x92 is an anion wherein X is independently a halogen; and xe2x80x9c*xe2x80x9d designates an asymmetric carbon having (R)- or (S)-configuration.
In the second step, Step (b), the didehydroamino acid ester (IV) is reduced with hydrogen gas. The reduction takes place in the presence of a rhodium catalyst. The selection of rhodium catalyst is critical to the enantioselective process of the invention. The rhodium catalyst may be present as (R,R) or (S,S) which is used to prepare either the enantiomerically enriched (R)-4-piperdinylglycine or (S)-4-piperdinylglycine, respectively. The rhodium catalyst is selected from the group consisting of (R,R)-BPE-Rh having the formula (A1), (S,S)-BPE-Rh having the formula (A2), (R,R)-DuPHOS-Rh having the formula (B 1), (S,S)-DuPHOS-Rh having the formula (B2), wherein R5 is independently selected from the group consisting of a C1-C8 linear, branched or cyclic alkyl group, a C1-C8 linear, branched or cyclic fluoroalkyl group, and combinations thereof, diene is a counter ligand independently selected from the group consisting of cyclooctadiene (COD) and norbornadiene (NBD). Axe2x88x92 is an anion wherein A is independently selected from the group consisting of trifluoromethanesulfonate (OTf), tetrafluoroborate (BF4), hexafluoroantimonate (SbF6) and hexafluorophosphate (PF6). The rhodium catalysts"" [(Me-BPE)-Rh-(COD)]OTf and [(Me-DuPHOS)-Rh-(COD)]OTf are commercially available from Strem Chemicals Inc. A combination of catalysts may also be used. 
Preferably, the rhodium catalyst is selected from [((R,R)-Me-BPE-Rh-(COD)]OTf, [((S,S)-Me-BPE-Rh-(COD)]OTf, [((R,R)-Me-DuPHOS-Rh-(COD)]OTf, or [((S,S)-Me-DuPHOS-Rh-(COD)]OTf having the respective formulas T1, T2, T3, T4, 
The reduction in Step (b) is preferably conducted at a temperature of from about 0xc2x0 C. to about 60xc2x0, more preferably, 20xc2x0 C. to 28xc2x0 C.; and under gaseous hydrogen pressure of from about 1 atm to about 200 atm, more preferably, 50 atm to 100 atm.
The reduction in Step (b) results in the formation of a protected compound having the formula (V) which contains an asymmetric carbon as designated by a xe2x80x9c*xe2x80x9d sign, 
In the compound of formula (V), R2 is selected from the group consisting of hydrogen, phenyl and a C1-C8 linear, branched or cyclic alkyl group. Preferably R2 is methyl. R3 and R4 are independently selected from the group consisting of hydrogen, phenyl, a C1-C8 linear, branched or cyclic alkyl group, and OR6, wherein R6 is selected from the group consisting of hydrogen, phenyl, benzyl, substituted benzyl, and C1-C8 linear, branched or cyclic alkyl group. Preferably, R3 is OCH2Ph. Preferably, R4 is OC(CH3)3.
In the third step, Step (c), at least one protecting group is removed from the protected compound formed in Step (b). In one embodiment of the invention, all three protecting groups are removed in one step from the compound of formula (V) to form the 4-piperidinylglycine having the formula (I).
In another embodiment of the invention, two protecting groups are removed from the compound of formula (V), whereby a semi-protected compound is formed having the formula (VII) 
wherein R4 is selected from the group consisting of hydrogen, phenyl, a C1-C8 linear, branched or cyclic alkyl group, and OR6, wherein R6 is selected from the group consisting of hydrogen, phenyl, benzyl, substituted benzyl, and C1-C8 linear, branched or cyclic alkyl group. Preferably, R4 is OC(CH3)3. In an optional fourth step, Step (d), the protecting group in formula (VII) is removed to form the 4-piperidinylglycine having the formula (I).
Following removal of at least one protecting group, the desired enantiomeric 4-piperidinylglycine may optionally be separated by physical or chemical means to increase the enantiomeric excess. Examples of such means for separation include, but are not limited to, crystallization, chemical resolution, and chiral preparative chromatography such as high pressure liquid chromatography (HPLC). An especially preferred means for increasing the enantiomeric excess is crystallization of the semi-protected 4-piperidinylglycine of formula (VII).
The above-mentioned steps are carried out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures, and at atmospheric or super-atmospheric pressure.
The compounds of the invention exhibit valuable pharmacological properties in mammals including man, particularly as inhibitors of TNF-xcex1-activity and as inhibitors of matrix-degrading metalloproteinase enzymes.
The following nonlimiting examples illustrate further aspects of the invention.